WO2007006197A1 - Utilisation de lévo-ornidazole pour la préparation de médicaments contre les infections parasitaires - Google Patents

Utilisation de lévo-ornidazole pour la préparation de médicaments contre les infections parasitaires Download PDF

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Publication number
WO2007006197A1
WO2007006197A1 PCT/CN2006/001204 CN2006001204W WO2007006197A1 WO 2007006197 A1 WO2007006197 A1 WO 2007006197A1 CN 2006001204 W CN2006001204 W CN 2006001204W WO 2007006197 A1 WO2007006197 A1 WO 2007006197A1
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ornidazole
preparation
infection
day
levo
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PCT/CN2006/001204
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English (en)
French (fr)
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Cang Zhang
Xiaoxin Tao
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Nanjing Sanhome Pharmaceutical Co., Ltd.
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Application filed by Nanjing Sanhome Pharmaceutical Co., Ltd. filed Critical Nanjing Sanhome Pharmaceutical Co., Ltd.
Priority to AT06742090T priority Critical patent/ATE493127T1/de
Priority to DE602006019250T priority patent/DE602006019250D1/de
Priority to US11/909,623 priority patent/US20080177083A1/en
Priority to EP06742090A priority patent/EP1902712B1/en
Publication of WO2007006197A1 publication Critical patent/WO2007006197A1/zh
Priority to US13/831,706 priority patent/US20130202698A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the application of L-nornidazole in the preparation of a medicament for anti-parasitic infection, in particular to making L-Odnidazole into a dosage form suitable for clinical use and for anti-parasitic infection, in particular, Trichomonas vaginalis infection and cecum
  • the dosage form preferably includes an oral preparation, an intravenous preparation, and a vaginal preparation.
  • Levodnidazole (1-(3-chloro-2-S-(-)hydroxypropyl)-2-methyl-5-nitroimidazole) is ornidazole (Ornisdazo le, CAS 16773-42-5)
  • the left-handed body, the sulphate is a nitroimidazole derivative, is a powerful anti-anaerobic and anti-protozoal infection drug, and is newly developed with a higher therapeutic effect, shorter course of treatment and better tolerance after the treatment of metronidazole.
  • a third-generation nitroimidazole derivative with a wider distribution in the body.
  • ornidazole The antimicrobial action of ornidazole is caused by the reduction of the nitro group in the molecule to an amino group in an anaerobic environment, or by interaction with cellular components through the formation of free radicals, resulting in the death of microorganisms.
  • the commercially available ornidazole preparations are mainly the ornidazole racemates.
  • there are patent applications for the left and right-handed ornidazole see CN 1400312A
  • no pharmacological agents for left and right-handed ornidazole and racemic ornidazole Comparative studies have never revealed the difference between their pharmacodynamic activities.
  • ornidazole has a good effect on the treatment of anaerobic infections, but there are also some adverse reactions.
  • the present inventors have found that the pharmacokinetics of levofloxacin is superior to that of dextrose ornidazole by pharmacokinetics, pharmacodynamics, toxicology, general pharmacology and the like of ornidazole. Ornidazole, and the central toxicity is lower than that of dextrose ornidazole and racemic ornidazole.
  • mice injected intravenously with levotonil The value was 332 mg/kg (95% confidence limit of 312-362 mg/kg), and the mice were injected intraperitoneally with LD 5 of L-nordazole. The value was 1378 mg/kg (95% confidence limit was 1244 ⁇ 1526 mg/kg), and the LD 50 value of orally administered ornidolazole in mice was 1069 mg/kg (95% confidence limit was 935. 3 - 1222 mg). /kg ). The mice were injected intravenously with LD 5 of racemic ornidazole.
  • the value is 306mg/kg (9 5 % confidence limit is 272 ⁇ 346fflg/kg), mice were injected intraperitoneally with LD 5 of racemic ornidazole. The value was 1115 mg/kg (95% confidence limit was 1026 ⁇ 1212 mg/kg), and the mice were administered LD 5 of racemic ornidazole by gavage. The value was 769. 4 mg/kg (95% confidence limit was 674.2 to 878. Omg/kg). It can be seen that the toxicity of L-Odazole is lower than that of racer ornidazole, and the safety is relatively high.
  • L-ornidazole in the treatment of parasitic infections, including mouse vaginal Trichomonas infection and mouse cecal amoe infection, and found that L-Oral Oxazole is superior to dextrozole and racer ornidazole in the treatment of parasitic infections, including mouse vaginal trichomonas infection and mouse cecal amoe infection.
  • the specific experiment is as follows:
  • mice Male ICR mice were intraperitoneally injected with 0.4 ⁇ ml of 3 ⁇ 10 6 Trichomonas vaginalis (from Trichomonas vaginalis). The mice were randomly divided into 19 groups, 10 in each group, of which vehicle control The group was injected with a blank solution through the tail vein, and the administration group was intravenously administered at 2, 24, 48, and 72 hours after infection. After 5 days of infection, the animals were sacrificed, the viscera was washed, and the washing solution was centrifuged for microscopic examination for the presence of active worms. An anatomical examination was performed to observe whether there was an abscess in the viscera and abdominal cavity of each group, and the number of live trichomoniasis in the tumor was examined under a microscope.
  • mice Male ICR mice were injected with 0.2 ml of cecal amoeba liquid containing about 200,000 units in the cecum. The mice were randomly divided into 19 groups, 10 in each group. The vehicle control group was injected with a blank solution through the tail vein. The drug group was administered intravenously at 24 48 72 hours after infection. Animals were sacrificed 6 days after infection, and cecal mucosal sections were taken for phase contrast studies of amoeba under the microscope. As a result, the amoeba was grown on the cecum of the vehicle control mice, and the amoeba was cleared by the administration group. The dose of 50% and 90% amoeba was inhibited, ie ED 5 . And ED 9 . , the results are shown in Table 2
  • L-Odazole is slightly better than D-Odazole and racemic ornidazole in the treatment of cecal amoeba infection in mice.
  • L-Odazole is slightly better than D-Odazole and racernidazole in the treatment of parasitic infections, including mouse Trichomonas vaginalis infection and mouse cecal amoe infection.
  • the pharmacokinetics of levofloxacin is better than that of dextrose ornidazole and racer ornidazole
  • the toxicity of middle scorpion is lower than that of dextronitazole and racer ornidazole. It is more practical for anti-parasitic infection drugs.
  • the present invention also provides a pharmaceutical preparation containing levofloxacin as a main drug, and preferably the preparation is an oral preparation, an intravenous preparation or a vaginal preparation.
  • Dosage of the oral preparation It is preferably 10 to 4 Q mg/kg/day, more preferably 20 to 30 mg/kg/day.
  • the intravenous administration preparation is preferably administered at a dose of 5 to 40 mg/kg/day, more preferably 10 to 20 mg/kg/day.
  • the vaginal administration preparation is preferably administered at a dose of 10 to 40 mg/kg/day, more preferably 20 to 30 mg/kg/day.
  • the prescription consists of:
  • 1000 tablets of levonordazole tablets are prepared.
  • the specific preparation method is as follows: First, the original auxiliary materials are passed through a 100 mesh sieve, and the prescribed amount of L-orthoside and pregelatinized starch are uniformly mixed, and 8% starch slurry is added. Soft materials, granulation, drying, whole granules, adding the prescribed amount of sodium carboxymethyl starch and magnesium stearate to the granules, tableting, coating with 8% Opadry 95% ethanol solution.
  • the specific preparation method is to first return the original excipients to 100 mesh, weigh the prescription amount of L-nordazole and starch, and add 6% starch pulp to make soft materials, granulate, dry, whole grain, and add to the granules.
  • the prescribed amount of magnesium stearate is evenly mixed and filled with plastic bottles.
  • the specific preparation method is to first return the original excipients to 100 mesh, and weigh the prescribed amount of L-nordazole, mannitol, icing sugar and sodium carboxymethyl starch, and add 8% starch slurry to make soft materials, granulation, Drying, whole grain, packaging.
  • the prescription consists of:
  • the specific preparation method is to first weigh the prescribed amount of L-nornidazole and sodium chloride, add 40" water for injection 8L, stir, dissolve; Lmol / L hydrochloric acid to adjust the pH to 4.0; add 40 ° C water for injection to the full amount; add 0.1% activated carbon to the above solution, stir, place for 15min, 5 ⁇ titanium rod decarbonization, and then through the cartridge filter 0.45 ⁇ and 0.22 ⁇ Microfiltration membrane fine filtration; potted in 100 ml glass infusion bottle, steam sterilization at 100 Torr for 45 min.
  • the specific preparation method is to take a prescribed amount of L-nordazole and glucose dissolved in 8 L of 45 Torr of water for injection, and adjust the pH to 3.5 with 0.1 mol/L hydrochloric acid. Add 45"C water for injection to the whole amount. Add G.15% activated carbon, stir, place for 15min, decarburize with 5 ⁇ titanium rod, finely filter through the microfiltration membrane of the barrel filter 0.45 ⁇ and 0.22 ⁇ , potting in 100ml glass In the infusion bottle, it is sterilized by flowing steam at 100 Torr for 45 minutes to obtain L-ornidazole glucose injection.
  • the specific preparation method is to weigh a prescribed amount of L-nordazole, dissolved in a prescription amount of about 45" C propylene glycol, add 100 ml of 45 water for injection, and stir well; adjust the pH to 4.5 with 0.1 mol/L hydrochloric acid. After dissolving, add 45 ⁇ C water for injection to the full amount; add 0.1% needle with activated carbon, stir, place for 15 min, deduct the carbon from 5 ⁇ titanium rod, and then finely filter through the microfiltration membrane of the cartridge filter 0.45 ⁇ and 0.22 ⁇ ; In the ampoule, it was sterilized by flowing steam at 100 Torr for 45 minutes to obtain L- ornidazole injection.
  • the prescription consists of:
  • the specific preparation method is to grind each raw and auxiliary materials in the prescription through 80 mesh sieve; weigh the prescription amount of L-nordazole, sodium lauryl sulfate, Sodium bicarbonate and 75% of the prescribed amount of microcrystalline cellulose, 80% of the prescription low-substituted hydroxypropyl cellulose are uniformly mixed, then made of 60% ethanol soft material, granulated with 14 mesh nylon sieve, and the wet granules are placed at 60 Dry in the oven at °C, until the water content is ⁇ 1.0%, take it out, and granulate it with a 12-mesh nylon sieve to obtain the granule A; weigh the prescribed amount of organic acid and the remaining prescription amount of microcrystalline cellulose, low-substituted hydroxypropyl cellulose, After mixing evenly, the soft material was made of 60% ethanol, and the granules were sieved with

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  • Tropical Medicine & Parasitology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Description

左旋奥硝唑在制备抗寄生虫感染的药物中的应用 技术领域
本发明涉及左旋奥硝唑在制备抗寄生虫感染的药物中的应用， 特 别涉及将左旋奥硝唑制成适合临床使用的剂型并用于抗寄生虫感染， 特别是***毛滴虫感染和盲肠阿米巴虫感染， 所述剂型优选包括口服 制剂、 静脉给药制剂及***给药制剂。
背景技术
左旋奥硝唑（ 1- ( 3-氯 -2- S- ( - )羟丙基） -2-甲基 -5-硝基咪唑 ) 为奥硝唑（Ornidazo le , CAS 16773-42-5 ) 的左旋体， 奥硝唾为硝基 咪唑类衍生物， 是一种强力抗厌氧菌及抗原虫感染的药物， 也是继曱 硝唑后新研制成的疗效更高、 疗程更短、 耐受性更好、 体内分布更广 的第三代硝基咪唑类衍生物。 奥硝唑的抗微生物作用是通过其分子中 的硝基在无氧环境中还原成氨基， 或通过自由基的形成与细胞成分相 互作用， 从而导致微生物的死亡。 市售奥硝唑制剂均以奥硝唑消旋体 为主药。 中国有从奥硝唑消旋体通过酶法拆分得左、 右旋奥硝唑（见 CN 1400312A )的专利申请， 但未对左、 右旋奥硝唑及消旋奥硝唑进行 药理药效比较研究， 也从未公开它们的药效活性之间的区别。
发明内容
临床使用表明奥硝唑具有很好的治疗厌氧菌感染的效果， 但也存 在一些不良反应。 本发明人通过对奥硝唑的左旋体进行药代动力学、 药效学、 毒理学、 一般药理学等试验研究， 发现左旋奥硝唑药代动力 学特性优于右旋奥硝唑和消旋奥硝唑， 且中枢毒性低于右旋奥硝唑和 消旋奥硝唑。
急性毒理研究显示小鼠静脉注射左旋奥硝唑的 LD5。值为 332mg/kg ( 95%可信限为 312 - 362mg/kg ) , 小鼠腹腔注射左旋奥硝唑的 LD5。值 为 1378 mg/kg ( 95%可信限为 1244 ~ 1526mg/kg )， 小鼠灌胃给药左旋 奥硝唑的 LD50值为 1069mg/kg ( 95%可信限为 935. 3 - 1222mg/kg )。 小 鼠静脉注射消旋奥硝唑的 LD5。值为 306mg/kg ( 95%可信限为 272 〜 346fflg/kg ) , 小鼠腹腔注射消旋奥硝唑的 LD5。值为 1115 mg/kg ( 95% 可信限为 1026 ~ 1212mg/kg ) , 小鼠灌胃给药消旋奥硝唑的 LD5。值为 769. 4mg/kg ( 95%可信限为 674. 2 ~ 878. Omg/kg )。 由此可见， 左旋奥 硝唑毒性作用比消旋奥硝唑更低， 安全性相对要高。
将左旋奥硝唑组、 右旋奥硝唑组和消旋奥硝唑组分别静脉给药 2 周对非啮齿类动物 Beagle 犬的毒性试验表明左旋奥硝唑与右旋奥硝 唑及消旋奥硝唑相比中枢毒性更低， 用药更加安全。
在一般药理作用试验中考察了左旋奥硝唑、 右旋奥硝唑及消旋奥 硝唑对小鼠中枢神经***的影响。 试验结果表明， 左旋奥硝唑对中枢 神经的抑制作用与右旋奥硝唑和消旋奥硝唑相比明显降 4氐。
基于上述实验， 发明人对左旋奥硝唑在治疗寄生虫感染 （包括小 鼠***毛滴虫感染和小鼠盲肠阿米巴虫感染） 的治疗作用方面进行了 药效学研究， 发现左旋奥硝唑在治疗寄生虫感染（包括小鼠***毛滴 虫感染和小鼠盲肠阿米巴虫感染） 的治疗作用方面要优于右旋奥硝唑 和消旋奥硝唑。 具体实验如下：
(一）对***毛滴虫引起感染的药效学研究
雄性 ICR小鼠， 分别腹腔注射含 3 X 106***毛滴虫的液体 0. 4ml (***毛滴虫取自临床患者） ， 将小鼠随机分为 19组， 每組 10只， 其中溶媒对照组经尾静脉注射空白溶液， 给药组分别于感染后 2、 24、 48、 72小时静脉注射给药。 于感染 5天后处死动物， 冲洗内脏， 沖洗 液经离心后镜检有无活动虫体。 进行解剖检查， 观察各组内脏和腹腔 是否出现脓肿， 显微镜下检查肿内的活滴虫数。 结果为溶媒对照组小 鼠腹腔和内脏均形成多发性小脓肿， 给药组小鼠脓肿被抑制， 活滴虫 数减少。 计算 50%和 90%阿米巴虫被抑制的药物剂量即 ED5。和 ED9。。 结 果见表 1。 表 1. 对***毛滴虫引起感染的药效学研究
药物 ED5 95%可信限 ED9 95%可信限
左旋奥硝唑 9.1 4.8-17.4 32.6 17.0~ 61.7
右旋奥硝唑 14.1 8.3-24.0 54.5 32.4 - 93.3
消旋奥硝唑 11.3 5.5-22.9 43.8 21.4-89.1
上述实验结果表明， 左旋奥硝唑在治疗小鼠***毛滴虫感染的治 疗作用方面要优于右旋奥硝唑和消旋奥硝唑。
(二）对盲肠阿米巴虫引起的感染的药效研究
雄性 ICR小鼠，在盲肠上注射 0.2ml含约 20万单位的痢疾阿米巴 虫液体， 将小鼠随机分为 19组， 每组 10只， 其中溶媒对照组经尾静 脉注射空白溶液，给药组分别于感染后 24 48 72小时静脉注射给药。 于感染 6天后处死动物， 取盲肠黏膜切片在显微镜下做阿米巴虫的阶 段对比性研究。结果为溶媒对照组小鼠的盲肠上有痢疾阿米巴虫生长， 而给药组小鼠可以清除阿米巴虫。计算 50%和 90%阿米巴虫被抑制的药 物剂量， 即 ED5。和 ED9。， 结果见表 2
表 2 . 对盲肠阿米巴虫引起的感染的药效学研 1究
i
药物 ED50 95%可信限 ED90 95%可信限
左旋奥硝唑 10.5 5.4 ~ 20.4 41.2 21.4-81.3 右旋奥硝唑 13.3 8.3~ 20.8 64.4
消旋奥硝唑 11.4 5.6-22.9 55.2
上述实验结果表明， 左旋奥硝唑在治疗小鼠盲肠阿米巴虫感染的 治疗作用方面略优于右旋奥硝唑和消旋奥硝唑。
通过上述实验表明左旋奥硝唑在治疗寄生虫感染 （包括小鼠*** 毛滴虫感染和小鼠盲肠阿米巴虫感染） 的治疗作用方面要略优于右旋 奥硝唑和消旋奥硝唑， 而左旋奥硝唑药代动力学特性优于右旋奥硝唑 和消旋奥硝唑， 且中柩毒性低于右旋奥硝唑和消旋奥硝唑， 故将左旋 奥硝唑制为抗寄生虫感染药物更具有实用性。
本发明还提供了含左旋奥硝唑为主药的药物制剂， 优选所述制剂 为口服制剂、 静脉给药制剂或***给药制剂。 所述口服制剂给药剂量 优选为 10~4Q mg/kg/天， 更优选为 20~ 30mg/kg/天。 所述静脉给药 制剂给药剂量优选为 5 ~ 40 mg/kg/天， 更优选为 10~ 20mg/kg/天。 所 迷***给药制剂给药剂量优选为 10~ 40 mg/kg/天， 更优选为 20~ 30mg/kg/天
具体实施方式
实施例 1:
处方組成为：
(a) 左旋奥硝唑 250mg/片
(b)预胶化淀粉 80mg/片
( c)羧甲基淀粉钠 4mg/片
(d)硬脂酸镁 3mg/片
以制成 1000片左旋奥硝唑片剂为例，具体制备方法是： 先将原辅 料过 100 目筛， 称取处方量的左旋奥硝唑和预胶化淀粉混合均匀， 加 8%淀粉浆制软材， 制粒， 烘干， 整粒， 向颗粒中加入处方量羧甲基淀 粉钠和硬脂酸镁， 压片， 用 8%的欧巴代 95%乙醇溶液包衣。
实施例 2:
处方组成：
(a ) 左旋奥硝唑 250mg/粒
(b) 淀粉 45mg/粒
( c)硬脂酸镁 2mg/粒
以制备 1000粒左旋奥硝唑胶嚢剂为例。 具体制备方法是先将原 辅料过 100目歸， 称取处方量的左旋奥硝唑和淀粉混合均勾， 加 6%淀 粉浆制软材， 制粒， 烘干， 整粒， 向颗粒中加入处方量硬脂酸镁混合 均匀， 充填胶嚢。
实施例 3:
处方组成：
( a) 左旋奥硝唑 250mg/袋
(b)甘露醇 250mg/袋
( c) 蔗糖 2QQmg/袋 (d)羧甲基淀粉钠 20mg/袋
以制备 1000袋左旋奥硝唑颗粒剂为例。具体制备方法是先将原辅 料过 100 目歸， 称取处方量的左旋奥硝唑、 甘露醇、 糖粉和羧甲基淀 粉钠混合均勾， 加 8%淀粉浆制软材， 制粒， 烘干， 整粒， 包装。
实施例 4:
处方組成为：
(a) 左旋奥硝'峻 5mg/ml
(b) 氯化钠 8.30mg/ml
(c) 注射用水加至 100ml
以制成 100瓶左旋奥硝唑氯化钠注射液制剂为例， 具体制备方法 是先称取处方量的左旋奥硝唑和氯化钠， 加 40" 注射用水 8L， 搅拌， 溶解； 用 0. lmol/L盐酸调 pH至 4.0; 加 40°C注射用水至全量； 向上 述溶液中加入 0.1%活性炭， 搅拌， 放置 15min, 5μπι钛棒脱炭，再经筒 式滤器 0.45μιη和 0.22μιη的微孔滤膜精滤； 灌封于 100ml玻璃输液瓶 中， 于 100Ό流动蒸汽灭菌 45min。
实施例 5:
处方组成：
(a) ： 左旋奥硝唑 5mg/ml
(b) ： 葡萄糖 50mg/ml
(c) ： 注射用水加至 100ml
以制备 100瓶左旋奥硝唑葡萄糖注射液为例。 具体制备方法是称 取处方量的左旋奥硝唑和葡萄糖溶于 8L 45Ό的注射用水中， 用 0. lmol/L的盐酸， 调节 pH至 3.5。 加 45"C注射用水至全量。加 G.15% 活性炭， 搅拌， 放置 15min, 5μιη钛棒脱炭，再经筒式滤器 0.45μηι和 0.22μιη的微孔滤膜精滤， 灌封于 100ml玻璃输液瓶中， 于 100 Ό流 动蒸汽灭菌 45min, 即得左旋奥硝唑葡萄糖注射液。
实施例 6:
处方组成：
(a) 左旋奥硝唑 25mg/ml (b) 丙二醇 0.5ml/ml
(c) 注射用水加至 10ml
以制备 100瓶左旋奥硝唑注射液为例。 具体制备方法是称取处方 量的左旋奥硝唑，溶于处方量的约 45"C的丙二醇中，加入 100ml的 45 注射用水， 搅匀； 用 0. lmol/L的盐酸调 pH至 4.5， 溶解后， 加 45 ■C注射用水至全量； 加入 0.1%针用活性炭， 搅拌， 放置 15min, 5μιη 钛棒脱炭，再经筒式滤器 0.45μιη和 0.22μιη的微孔滤膜精滤； 灌封于 安瓿瓶中， 于 100 Ό流动蒸汽灭菌 45min, 即得左旋奥硝唑注射液。
实施例 7:
处方組成为：
(a)奥硝唑 500mg/片
(b)碳酸氢钠 300mg/片
( c ) 低取代羟丙基纤维素 lOOmg/片
( d ) 十二烷基硫酸钠 3· 2mg/片
(e)微晶纤维素 440mg/片
(f ) 酒石酸 280mg/片
(g) 聚乙二醇 16mg/片
以制成 100片左旋奥硝唑***泡腾片制品为例， 具体制备方法是 将处方中各原辅料分别研磨过 80目筛；称取处方量左旋奥硝唑、十二 烷基硫酸钠、 碳酸氢钠及 75%处方量微晶纤维素、 80%处方量低取代羟 丙基纤维素混合均匀后， 用 60%乙醇制软材， 用 14目尼龙筛制粒， 将 湿颗粒置于 60°C烘箱中干燥， 至水分 <1.0%时， 取出， 用 12目尼龙筛 整粒， 得颗粒 A; 称取处方量有机酸及剩余处方量微晶纤维素、 低取 代羟丙基纤维素， 混合均匀后， 用 60%乙醇制软材， 并用 14 目尼龙筛 制粒， 将湿颗粒放置于 60Ό烘箱中干燥， 至水分 < 1.5%， 取出， 用 12 目尼龙筛整粒， 得颗粒 B; 将颗粒 A和颗粒 B及处方量聚乙二醇混合 均匀； 用异形冲头压片、 包装， 即得。

Claims

权 利 要 求
1. 左旋奥硝唑在制备抗寄生虫感染的药物中的应用。
2. 根据权利要求 1所述的用途，其特征在于将左旋奥硝唑制为适 合临床使用的抗寄生虫感染的药物制剂， 所述制剂包括口服制剂、 静 脉给药制剂及***给药制剂。
3. 根据权利要求 2 所述的用途， 其特征在于所述口服制剂给药 剂量优选为 10~ 40 mg/kg/天， 更优选为 20~ 30mg/kg/天。
4. 根据权利要求 2 所述的用途， 其特征在于所述静脉给药制剂 给药剂量优选为 5~ 40 mg/kg/天， 更优选为 10~20mg/kg/天。
5. 根据权利要求 1 - 4任一项所述的用途， 其特征在于所述*** 给药制剂给药剂量优选为 10~40 mg/kg/天， 更优选为 20~ 30nig/kg/ 天。
6. 根据权利要求 1 -4任一项所述的用途， 其特征在于所述寄生 虫感染为***毛滴虫感染。
7. 根据权利要求 1 -4任一项所述的用途， 其特征在于所述寄生 虫感染为盲肠阿米巴虫感染。
PCT/CN2006/001204 2005-07-08 2006-06-05 Utilisation de lévo-ornidazole pour la préparation de médicaments contre les infections parasitaires WO2007006197A1 (fr)

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US11/909,623 US20080177083A1 (en) 2005-07-08 2006-06-05 Use of Levo-Ornidazole For Preparing Anti-Parasitic Infection Drug
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